What are the recommended dosing regimens for antiviral medications, such as entecavir (Entecavir) or tenofovir disoproxil fumarate (TDF) (Tenofovir), in patients with hepatitis B and hepatitis C?

Dosing in Hepatitis B and C

Hepatitis B: Preferred First-Line Agents and Dosing

For chronic hepatitis B, entecavir (0.5 mg daily), tenofovir disoproxil fumarate (TDF 300 mg daily), or tenofovir alafenamide (TAF 25 mg daily) are the recommended first-line monotherapies due to their high potency and minimal resistance risk. 1

Standard Dosing Regimens

Entecavir:

• Treatment-naïve patients: 0.5 mg once daily orally 1
• Lamivudine-refractory patients or those with decompensated cirrhosis: 1 mg once daily 1
• Long-term treatment until HBsAg loss (potentially indefinite for most patients) 1

Tenofovir Disoproxil Fumarate (TDF):

• Adults and pediatric patients ≥12 years weighing ≥35 kg: 300 mg once daily 2, 3, 4
• Adolescents (12-18 years): Alternative dosing of 8 mg/kg daily (maximum 300 mg) 3
• Taken orally without regard to food 4

Tenofovir Alafenamide (TAF):

• Adults: 25 mg once daily 1, 2
• Preferred over TDF in patients with renal or bone concerns 1
• Noninferior efficacy to TDF at 48,96, and 144 weeks 2, 5

Dose Adjustments for Renal Impairment

Critical for TDF (TAF and entecavir require less adjustment): 1, 3

• CrCl ≥50 mL/min: TDF 300 mg every 24 hours 3, 4
• CrCl 30-49 mL/min: TDF 300 mg every 48 hours 3, 4
• CrCl 10-29 mL/min: TDF 300 mg every 72-96 hours 3, 4
• Hemodialysis: TDF 300 mg every 7 days or after approximately 12 hours of dialysis 3, 4

TAF dosing adjustments: 1

• No dose adjustment needed for CrCl ≥15 mL/min
• Not recommended for CrCl <15 mL/min without hemodialysis 1

Entecavir: Requires dose adjustment for CrCl <50 mL/min 1

Patient-Specific Selection Criteria

Choose TAF, entecavir, or besifovir over TDF in patients with: 1, 3

• Baseline eGFR <60 mL/min
• Proteinuria or albuminuria >0.5 mg/dL
• Hypophosphatemia <2.5 mg/dL
• Uncontrolled diabetes or hypertension
• Osteopenia, osteoporosis, or chronic steroid use
• Advanced age
• Pre-existing renal dysfunction or metabolic bone disease 1

Rationale: In a 96-week trial, patients with risk factors on TDF had median eGFR decline of -5.0 mL/min versus -0.3 mL/min with TAF, and bone mineral density changes were -3.29% with TDF versus +1.23% with TAF 3

Treatment Duration and Monitoring

Duration: 1, 3

• Long-term until HBsAg loss (potentially lifelong for most patients) 1
• HBeAg-positive patients: Minimum 1 year, continuing at least 1 year after HBeAg seroconversion 3
• HBeAg-negative patients: Typically indefinite 3
• Compensated cirrhosis: Long-term (potentially lifelong) 1, 6
• Decompensated cirrhosis: Indefinite (lifelong) mandatory 1, 6

Monitoring requirements: 2, 3, 4

• Baseline: Creatinine clearance, serum phosphorus, urine glucose, urine protein, hepatitis B and HIV testing 2, 4
• During treatment: Periodic ALT, HBV DNA, renal function, and bone density (if risk factors present) 3
• After discontinuation (only if HBsAg loss achieved): Liver function tests every 1-3 months initially, HBV DNA every 2-6 months 6

Switching Strategies for Adverse Effects

If renal dysfunction or bone disease develops on TDF: 1, 3

• Switch to TAF, entecavir, or besifovir depending on treatment history 1
• After switching from TDF to TAF, eGFR improved from -4.6 mL/min decline to -0.06 mL/min by week 144 1, 3
• Bone mineral density significantly improved after switching to TAF 1, 3

Resistance Management

Lamivudine is NOT recommended as first-line therapy due to high resistance rates (up to 70% at 5 years). 1 Similarly, adefovir and telbivudine are not recommended 1

For patients with resistance: 1

• Lamivudine/telbivudine resistance: Switch to TDF or TAF 1
• Entecavir resistance: Switch to TDF or TAF, or combine with TDF/TAF 1
• Adefovir resistance: Switch to entecavir or TDF/TAF 1
• Multidrug resistance: Combine entecavir and TDF/TAF 1, 7, 8

In rescue therapy studies, entecavir plus TDF combination achieved HBV DNA <50 IU/mL in 76% at week 48 and 85% at week 96, regardless of prior resistance patterns 7, 8

Critical Safety Warnings

Severe acute exacerbations of hepatitis B can occur after discontinuing any antiviral therapy. 1, 2, 4 Monitor hepatic function closely with clinical and laboratory follow-up for at least several months after discontinuation 2, 4

Lactic acidosis risk: Discontinue treatment if symptoms or laboratory findings suggest lactic acidosis or pronounced hepatotoxicity 4

HIV testing mandatory: All HBV-infected patients must be tested for HIV before initiating therapy, as monotherapy in HIV/HBV coinfection can lead to HIV resistance 1, 4

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Hepatitis C: No Direct Evidence Provided

The evidence provided focuses exclusively on hepatitis B treatment. For hepatitis C, direct-acting antivirals (DAAs) are the standard of care, but specific dosing regimens are not addressed in the available evidence. Current HCV treatment does not typically involve entecavir or tenofovir monotherapy as these are HBV-specific agents.

Common Pitfalls to Avoid

1. Do not use lamivudine, adefovir, or telbivudine as first-line therapy due to high resistance rates 1
2. Do not forget renal dose adjustments for TDF - failure to adjust can lead to nephrotoxicity 3, 4
3. Do not use peginterferon in decompensated cirrhosis - it is contraindicated due to risk of liver failure 1
4. Do not stop treatment without achieving HBsAg loss - high relapse rates occur, especially in HBeAg-negative disease 1, 6
5. Do not use TDF in patients with significant renal or bone disease risk factors - choose TAF or entecavir instead 1, 3